NM_001383.6:c.470C>T

Variant names:

• chr17-2036598-C-T
• rs116911386
• NM_001383.6:c.470C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001383.6(DPH1):​c.470C>T​(p.Thr157Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00663 in 1,614,134 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (51 hom.)
• Consequence: DPH1 NM_001383.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.16
• Publications: 11 publications found

Genes affected

DPH1 (HGNC:3003): (diphthamide biosynthesis 1) The protein encoded by this gene is an enzyme involved in the biosynthesis of diphthamide, a modified histidine found only in elongation factor-2 (EEF2). Diphthamide residues in EEF2 are targeted for ADP-ribosylation by diphtheria toxin and Pseudomonas exotoxin A. Defects in this gene have been associated with both ovarian cancer and autosomal recessive intellectual disability with short stature, craniofacial, and ectodermal anomalies. [provided by RefSeq, Oct 2016]

DPH1 Gene-Disease associations (from GenCC):

• developmental delay with short stature, dysmorphic facial features, and sparse hair

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• developmental delay with short stature, dysmorphic facial features, and sparse hair 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• craniofacial dysplasia-short stature-ectodermal anomalies-intellectual disability syndrome

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010593861).
• BP6: Variant 17-2036598-C-T is Benign according to our data. Variant chr17-2036598-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 445317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00573 (872/152312) while in subpopulation NFE AF = 0.00889 (605/68024). AF 95% confidence interval is 0.00831. There are 0 homozygotes in GnomAd4. There are 399 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 51 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001383.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPH1	NM_001383.6	MANE Select	c.470C>T	p.Thr157Ile	missense	Exon 5 of 13	NP_001374.4	Q9BZG8-4
	DPH1	NM_001346574.1		c.485C>T	p.Thr162Ile	missense	Exon 5 of 13	NP_001333503.1
	DPH1	NM_001346575.1		c.485C>T	p.Thr162Ile	missense	Exon 5 of 13	NP_001333504.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPH1	ENST00000263083.12	TSL:1 MANE Select	c.470C>T	p.Thr157Ile	missense	Exon 5 of 13	ENSP00000263083.7	Q9BZG8-4
	DPH1	ENST00000575667.6	TSL:1	n.357C>T		non_coding_transcript_exon	Exon 4 of 12	ENSP00000460431.2	A0A0A0MTR4
	DPH1	ENST00000674200.2		c.485C>T	p.Thr162Ile	missense	Exon 5 of 13	ENSP00000501368.1	Q9BZG8-1

Frequencies

GnomAD3 genomes AF: 0.00573 AC: 872 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00889

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00596 AC: 1486 AN: 249438 AF XY: 0.00617

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00374

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00297

Gnomad NFE exome AF: 0.00834

Gnomad OTH exome AF: 0.00743

GnomAD4 exome AF: 0.00672 AC: 9827 AN: 1461822 Hom.: 51 Cov.: 31 AF XY: 0.00671 AC XY: 4883 AN XY: 727212

African (AFR) AF: 0.00111 AC: 37 AN: 33480

American (AMR) AF: 0.00382 AC: 171 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 411 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00451 AC: 389 AN: 86258

European-Finnish (FIN) AF: 0.00253 AC: 135 AN: 53376

Middle Eastern (MID) AF: 0.0111 AC: 64 AN: 5768

European-Non Finnish (NFE) AF: 0.00740 AC: 8225 AN: 1111990

Other (OTH) AF: 0.00652 AC: 394 AN: 60392

GnomAD4 genome AF: 0.00573 AC: 872 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.00536 AC XY: 399 AN XY: 74464

African (AFR) AF: 0.00120 AC: 50 AN: 41572

American (AMR) AF: 0.00614 AC: 94 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4828

European-Finnish (FIN) AF: 0.00377 AC: 40 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00889 AC: 605 AN: 68024

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00774 Hom.: 10

Bravo AF: 0.00552

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00118 AC: 5

ESP6500EA AF: 0.00994 AC: 84

ExAC AF: 0.00608 AC: 736

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0113

EpiControl AF: 0.0114

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L
PhyloP100		2.2
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.038
Sift	Benign	0.16	T
Sift4G	Benign	0.15	T
Polyphen		0.0010	B
Vest4		0.35
MVP		0.40
MPC		0.15
ClinPred		0.0089	T
GERP RS		4.4
Varity_R		0.059
gMVP		0.49
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs116911386; hg19: chr17-1939892; COSMIC: COSV99559516; COSMIC: COSV99559516;